Method and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonist

ABSTRACT

The invention relates to methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof, employing two or more agents or compounds to provide a triple site action on 5-HT 3  receptors, 5-HT 4  receptors, and at least one of H 2  receptors and proton pumps.

This Appln claims benefit of Prov. No. 60/122,394 filed Mar. 2, 1999.

1. Field of the Invention

The invention relates to methods and compositions for the prevention,treatment, or management of gastrointestinal disorders or symptomsthereof, by administering one or more agent(s) or compound(s) thatsimultaneously or sequentially act on a 5-HT₃ receptor, a 5-HT₄receptor, and either an H₂ receptor or a proton pump.

2. Background of the Invention

Gastrointestinal disorders are common disorders that affect thegastrointestinal tract, i.e., the stomach and intestines. Variousgastrointestinal disorders exist, including: gastro-esophageal refluxdisease, emesis, gastrointestinal motility dysfunction, gastrointestinalulcers, pathological hypersecretory conditions, and gastrichyperacidity. These diseases may be treated by various non-invasivemeans, such as administering to a patient a therapeutic agent, such asZANTAC® (ranitidine), TRITEC® (ranitidine), AXID® (nizatidine), TAGAMET®(cimetidine), PREVACID® (lansoprazole), PEPCID®, PEPCID AC® ACIDCONTROLLER™, MYLANTA AR ACID REDUCER™ (famotidine), PRILOSEC®(omeprazole), and others. New pharmaceutical compounds and preparationsare continually being developed.

U.S. Pat. Nos. 4,962,115, 5,057,525, and 5,137,896 (collectively “VanDaele”) disclose N-(3-hydroxy-4-piperidenyl)benzamides. These compoundsare said to stimulate the motility of the gastrointestinal system. VanDeale states that the cis and trans diastereomeric racemates of thesecompounds may be obtained separately by conventional methods, and thecis and trans diastereomeric racemates may be further resolved intotheir optical isomers. One such racemate, Cisapride, is chemically namedcis4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.Schapira et al., Acta Gastroenterolog. Belg., LIII:446-457 (1990).Cisapride is used primarily to treat gastroesophageal reflux disease(“GERD”), which is characterized as the backward flow of the stomachcontents into the esophagus. Cisapride is commercially available as theracemic mixture of the cis(−) and cis(+) diastereomeric enantiomers ofcisapride known as PROPULSID®.

Benzamide derivatives have several prominent pharmacological actions dueto their effects on neuronal systems modulated by the neurotransmitterserotonin. It has been reported that a major site of production andstorage of serotonin is the enterochromaffin cell of thegastrointestinal mucosa. It was also reported that serotonin provides apowerful intestinal transit and decreasing absorption time, as occurswith diarrhea. This stimulating action is also associated with nauseaand vomiting.

Because of their modulation of the serotonin neuronal system in thegastrointestinal tract, some benzamide derivatives are effectiveantiemetic agents and are used to control vomiting during cancerchemotherapy or radiotherapy. Costall et al., Neuropharmacology,26:1321-1326 (1987). This action is the result of an ability to blockserotonin at specific sites, particularly Type-3 5-hydroxytryptamine(5-HT₃) receptors. Clarke et al., Trends in Pharmacological Sciences,10:385-386 (1989). Chemotherapy and radiation therapy can induce nauseaand vomiting by damaging enterochromaffin cells in the gastrointestinaltract. As a result, the neurotransmitter serotonin is released andstimulates both afferent vagal nerve fibers (thus initiating thevomiting reflex) and serotonin receptors in the chemoreceptor triggerzone of the area postrema region of the brain. The anatomical site forthis action of the benzamide derivatives, and whether such action iscentral (CNS), peripheral, or a combination thereof, remains unresolved.Barnes et al., J. Pharm. Pharmacol., 40:586-588 (1988).

A second prominent action of certain benzamide derivatives is inaugmenting gastrointestinal smooth muscle activity from the esophagus tothe proximal small bowel, thus accelerating esophageal and smallintestinal transit, as well as facilitating gastric emptying andincreasing lower esophageal sphincter tone. Decktor et al., Eur. J.Pharmacol., 147: 313-316 (1988). Although the benzamide derivatives arenot cholinergic receptor agonists per se, the aforementioned smoothmuscle effects may be blocked by muscarinic receptor blocking agentssuch as atropine or inhibitors of neuronal transmissions, such as thetetrodotoxin type that block sodium channels. Fernandez and Massingham,Life Sci., 36: 1-14 (1985). Similar blocking activity has been reportedfor the contractile effects of serotonin in the small intestine. Craigand Clarke, Brit. J. Pharmacol., 96: 247P (1989). It is believed thatthe primary smooth muscle effects of some benzamide derivatives are theresult of an agonist action upon a class of serotonin receptors referredto as 5-HT₄ receptors, which are located on interneurons in themyenteric plexus of the gut wall. Clarke et al., Trends inPharmacological Sciences, 10: 385-386 (1989) and Dumuis et al., N. S.Arch. Pharmacol., 340: 403-410 (1989). Activation of these receptorssubsequently enhances the release of acetylcholine from parasympatheticnerve terminals located near surrounding smooth muscle fibers. It is thecombination of acetylcholine with its receptors on smooth musclemembranes which is the actual trigger for muscle contraction.

It has been reported that cisapride enters the central nervous systemand binds to 5-HT₄ receptors. This indicates that cisapride may havecentrally-mediated effects. Cisapride is a potent ligand at 5-HT₄receptors, which are located in several areas of the central nervoussystem. Dumuis et al., N. S. Arch. Pharmacol., 340: 403-410 (1989).Modulation of serotonergic systems may have a variety of behavioraleffects.

The co-administration of racemic cisapride with other therapeutic agentscauses inhibitory problems with the metabolism of cisapride by theliver. For example, ketoconazole has a pronounced effect on cisapridekinetics resulting from the inhibition of the metabolic elimination ofcisapride and leads to an 8-fold increase of the steady-state plasmalevels. Physician's Desk Reference®, Medical Economics Co., Inc., p.1308-1309, 52^(nd) Edition (1998). Interaction of racemic cisapride andother therapeutic agents can also potentiate cardiovascular sideeffects, such as cardiotoxicity. This potentiation occurs when otherdrugs present in the patient's system interfere with the metabolism ofcisapride, thereby causing a build up of racemic cisapride in the body.

These interactions are a significant drawback to the use of racemiccisapride; in particular, because racemic cisapride is often usedbefore, with, or immediately after another therapeutic agent. Inaddition, administration of racemic cisapride to a human has been foundto cause adverse effects such as cardiac arrhythmia, includingventricular tachycardia, ventricular fibrillation, Q_(T) prolongation,and torsades de pointes, central nervous system (“CNS”) effects,increased systolic pressure, interactions with other drugs, diarrhea,abdominal cramping, and cardiac depression.

Racemic cisapride in humans is metabolized mainly by oxidativeN-dealkylation of the piperidine nitrogen or by aromatic hydroxylationoccurring on either the 4-fluorophenoxy or benzamide rings. Meuldermanset al., Drug Metab. Dispos., 16(3):410-419 (1988); and Meuldermans etal., Drug Metab. Dispos., 16(3):403-409 (1988). Norcisapride, chemicallynamed 4-amino-5-chloro-N-(3-methoxy-4-piperidinyl)-2-methoxybenzamide,is an active metabolite of cisapride.

Recently, investigators have reported that the optically pure (+)stereoisomer of the cisapride metabolite norcisapride exhibits manyuseful characteristics, but without certain side effects of racemiccisapride. Specifically, U.S. Pat. No. 5,739,151 discloses a method ofeliciting an antiemetic effect and treating other conditions usingoptically pure (+) norcisapride.

Other agents or compounds which have been studied for the treatment ofgastrointestinal diseases include proton pump inhibitors and H₂ receptorantagonists. Proton pump inhibitors treat gastrointestinal diseases byinhibiting H⁺-K⁺ ATPase and thereby regulating acidity in gastricjuices. H₂ receptor antagonists inhibit histamine binding with H₂receptors to regulate gastric acid secretion. Goodman & Gilman, ThePharmacological Basis of Therapeutics, 9^(th) Edition, pp. 901-915(1996).

The concentration gradients of gastric acids across cell membranes varywidely. Perhaps the largest gradient in the body occurs across theplasma membrane of the parietal cells of the stomach lining, whichsecrete hydrochloric acid into gastric juice. Since the concentration ofhydrochloric acid in gastric juice may be as high as 0.1 M and theconcentration of H⁺ in the cells is about 10⁻⁷ M, parietal cells cansecrete H⁺ ions against a concentration gradient of about 1 millionto 1. A membrane-bound enzyme called H⁺-K⁺ ATPase facilitates activetransport of H⁺ across membranes against concentration gradients inexchange for K⁺ to form gastric hydrochloric acid. For each molecule ofcytosolic ATP hydrolyzed to ADP and phosphate, 2 H⁺ ions are transportedacross the plasma membrane from the cytosol to the stomach. Goodman &Gilman, The Pharmacological Basis of Therapeutics, 9^(th) Edition, pp.901-915 (1996).

Proton pump inhibitors suppress gastric acid secretion, the final stepof acid production, by specific inhibition of the H⁺-K⁺ ATPase enzymesystem at the secretory surface of gastric parietal cells. Proton pumpinhibitors include benzimidazole compounds, for example, omeprazole(PRILOSEC®), lansoprazole (PREVACID®), and pantoprazole. These protonpump inhibitors contain a sulfinyl group situated between substitutedbenzimidazole and pyridine rings. At neutral pH, omeprazole,lansoprazole, and pantoprazole are chemically stable, lipid soluble,weak bases that are devoid of inhibitory activity. These uncharged weakbases reach parietal cells from the blood and diffuse into the secretorycanaliculi, where the drugs become protonated and thereby trapped. Theprotonated species rearranges to form a sulfenic acid and a sulfenamide,the latter species capable of interacting with sulfhydryl groups ofH⁺-K⁺ ATPase. Full inhibition occurs with two molecules of inhibitor permolecule of enzyme. The specificity of the effects of proton pumpinhibitors is believed to derive from: a) the selective distribution ofH⁺-K⁺ ATPase; b) the requirement for acidic conditions to catalyzegeneration of the reactive inhibitor; and c) the trapping of theprotonated drug and the cationic sulfenamide within the acidiccanuliculi and adjacent to the target enzyme. Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9^(th) Edition, pp. 901-915(1996).

H₂ receptor antagonists competitively inhibit the interaction ofhistamine with H₂ receptors. They are highly selective and have littleor no effect on H₁ receptors. Although H₂ receptors are present innumerous tissues, including vascular and bronchial smooth muscle, H₂receptor antagonists interfere remarkably little with physiologicalfunctions other than gastric acid secretion. H₂ receptor antagonistsinclude nizatidine (AXID®), ranitidine (ZANTAC® and TRITEC®), famotidine(PEPCID AC®), and cimetidine (TAGAMET®). Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9^(th) Edition, pp. 901-915(1996).

H₂ receptor antagonists inhibit gastric acid secretion elicited byhistamine, other H₂ agonists, gastrin, and, to a lesser extent,muscarinic agonists. H₂ receptor antagonists also inhibit basal andnocturnal acid secretion, and this effect contributes in a major way totheir clinical efficacy.

Although therapeutic agents are available, there remains a need for amore effective, broad-spectrum treatment or therapy for gastrointestinaldisorders. For example, it is desirable to have safe and effectivemethods and compositions for preventing, treating, and managinggastrointestinal disorders without adverse effects or adverse drug-druginteractions.

3. SUMMARY OF THE INVENTION

The invention encompasses the prevention, treatment, or management ofgastrointestinal disorders by biological action at three differentsites: action at 5-HT₃ receptors, 5-HT₄ receptors, and either H₂receptors or proton pumps. The use of triple action is considered toprovide an unexpectedly superior therapeutic profile. The use of thistriple action therapy can be less toxic and/or more potent forpreventing, treating, and managing gastrointestinal disorders than theuse of agents that act on any of the three sites alone.

In one embodiment, three therapeutic agents or compounds are used, oneproviding action at 5-HT₃ receptors, another providing action at 5-HT₄receptors, and the third being either a proton pump inhibitor or an H₂receptor antagonist. For example, in a preferred embodiment, cisapride,ondansetron, and either a proton pump inhibitor or an H₂ receptorantagonist are used to prevent, treat, or manage gastrointestinaldisorders. In a more preferred embodiment, either optically pure (+)cisapride or optically pure (−) cisapride, or a pharmaceuticallyacceptable salt thereof, optically pure R(+) ondansetron, or apharmaceutically acceptable salt thereof, and either a proton pumpinhibitor or an H₂ receptor antagonist are used.

In another embodiment, the invention encompasses the synergistic use oftwo or more agents or compounds to provide triple site action on 5-HT₃receptors, 5-HT₄ receptors, and either H₂ receptors or proton pumps. Ina preferred embodiment, two agents or compounds are used, one providingdual action at 5-HT₃ receptors and 5-HT₄ receptors, and anotherproviding action either at H₂ receptors or proton pumps. For example, inthis preferred embodiment, optically pure (+) norcisapride, or apharmaceutically acceptable salt thereof, which has both 5-HT₃ and 5-HT₄activity, and either a proton pump inhibitor or H₂ receptor antagonistare used to prevent, treat, or manage gastrointestinal disorders.

This invention also encompasses the use of two separate pharmaceuticalcompositions adapted for the prevention, treatment, or management of apatient suffering from gastrointestinal disorders or symptoms thereof,one which comprises a therapeutically effective amount of optically pure(+) norcisapride, or a pharmaceutically acceptable salt thereof, andanother which a therapeutically effective amount of either a proton pumpinhibitor or H₂ receptor antagonist.

Alternatively, the invention also encompasses pharmaceuticalcompositions comprising optically pure (+) norcisapride, or apharmaceutically acceptable salt thereof in combination with a either aproton pump inhibitor or an H₂ receptor antagonist. Such single unitdosage forms comprise from about 0.5 mg to about 500 mg of opticallypure (+) norcisapride, or a pharmaceutically acceptable salt thereof,and from about 1 mg to about 200 mg of a proton pump inhibitor or fromabout 1 mg to about 2400 mg an H₂ receptor antagonist, in a suitablecarrier.

The pharmaceutical compositions and methods of the invention,particularly those which comprise a therapeutically effective amount ofoptically pure (+) norcisapride, or a pharmaceutically acceptable saltthereof, can be used to prevent or alleviate symptoms ofgastrointestinal disorders, while reducing or avoiding adverse effectsassociated with administration of conventional treatments such asconventional 5-HT₃ receptor antagonists, 5-HT₄ receptor agonists orantagonists, H₂ receptor antagonists, and proton pump inhibitors.Moreover, the compositions and methods of the present inventionencompass the treatment, prevention or management of gastrointestinaldisorders while reducing or avoiding adverse drug-drug interactionswhich are known to occur with the use of existing commercial agents,such as racemic cisapride.

4. DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses the prevention, treatment, or management ofgastrointestinal disorders by biological action at three differentsites, action on 5-HT₃ receptors, 5-HT₄ receptors, and either H₂receptors or proton pumps (e.g., inhibition of H⁺-K⁺-ATPase enzymesystem). The use of triple-site action is considered to provide anunexpectedly superior therapeutic profile to conventional treatment ofgastrointestinal disorders. The use of this triple action therapy can besafer and/or more effective for preventing, treating, and managinggastrointestinal disorders than the use of agents that act on any of thethree sites alone.

More specifically, the invention also encompasses the use of at leastthree agents or compounds to prevent, treat, or manage gastrointestinaldisorders, or symptoms thereof, one providing action at 5-HT₃ receptors,another providing action at 5-HT₄ receptors, and a third providingaction at either proton pump systems or H₂ receptors. Preferably, thethree compounds are cisapride, ondansetron, and either a proton pumpinhibitor or an H₂ receptor antagonist. More preferably, the threecompounds are either optically pure (+) cisapride or optically pure (−)cisapride, or a pharmaceutically acceptable salt thereof, optically pureR(+) ondansetron or a pharmaceutically acceptable salt thereof, andeither a proton pump inhibitor or H₂ receptor antagonist.

The invention also encompasses the synergistic use of at least twoagents or compounds to provide triple action on 5-HT₃ receptors, 5-HT₄receptors, and either H₂ receptors or the proton pump mechanism in theprevention, treatment, or management of gastrointestinal disorders.Preferably, two agents or compounds are used, one providing dual actionat 5-HT₃ receptors and 5-HT₄ receptors, and another providing action ateither H₂ receptors or proton pump systems. More preferably, the twoagents or compounds are optically pure (+) norcisapride, or apharmaceutically acceptable salt thereof, and either an H₂ receptorantagonist or a proton pump inhibitor.

Gastrointestinal disorders that can be treated by the compositions andmethods of the invention include, but are not limited to, disorders ofthe upper and lower gastrointestinal system, gastro-esophageal refluxdisease (“GERD”), emesis, gastrointestinal motility dysfunction,gastrointestinal ulcers, pathological hypersecretory conditions, andgastric hyperacidity. The gastrointestinal disorders additionallyinclude, but are not limited to, dyspepsia, gastroparesis, constipation,post-operative ileus, intestinal pseudo obstruction, gastric ulcers,duodenal ulcers, heartburn, acid indigestion, erosive esophagitis, sourstomach, upset stomach and Zollinger-Ellison Syndrome.

In a most preferred embodiment, the invention encompasses the use of theoptically pure (+) norcisapride, or a pharmaceutically acceptable saltthereof, and at least one of a proton pump inhibitor or an H₂ receptorantagonist, in preventing, treating, or managing gastrointestinaldisorders, or symptoms thereof. It should be noted that racemicnorcisapride, or a pharmaceutically acceptable salt thereof, may be usedas an alternative to optically pure (+) norcisapride in the methods andcompositions of the invention, although optically pure (+) norcisaprideis preferred. Similarly, optically pure stereoisomers or activemetabolites of the proton pump inhibitors or the H₂ antagonists may alsobe use as alternatives where appropriate, as well as pharmaceuticallyacceptable salts thereof. Specific examples by way of illustration onlyare set forth herein.

Without being limited by theory, it is believed that utilization of anagent or compound having dual activity as a 5-HT₃ receptor antagonistand a 5-HT₄ receptor agonist along with either a proton pump inhibitoror an H₂ receptor antagonist provides triple-site action, whichsurprisingly results in clearer dose-related definitions of efficacy,diminished adverse effects, a superior therapy due to synergisticactivity, and accordingly, an improved therapeutic index. For example,optically pure (+) norcisapride has dual activity as a 5-HT₃ receptorantagonist and a 5-HT₄ receptor agonist, and triple-site action isachieved when used with either a proton pump inhibitor or an H₂ receptorantagonist. It is, therefore, more desirable to use the compositions andmethods of the invention than to use a 5-HT₃ receptor antagonist, a5-HT₄ receptor agonist, an agent or compound having dual activity as a5-HT₃ receptor antagonist and a 5-HT₄ receptor agonist, a proton pumpinhibitor, or an H₂ receptor antagonist alone.

The use of the optically pure (+) norcisapride, or a pharmaceuticallyacceptable salt thereof, with either a proton pump inhibitor or an H₂receptor antagonist, in preventing, treating, or managinggastrointestinal disorders, in accordance with the present invention isconsider to reduce or avoid adverse effects associated with existingcommercial treatment for gastrointestinal disorders, such as racemiccisapride. Further, this embodiment is considered to reduce or avoidadverse drug-drug interactions associated with racemic cisapride.

The invention also encompasses methods of preventing, treating, ormanaging a condition caused by a dysfunction of 5-HT₃ receptors, 5-HT₄receptors, or proton pumps or H₂ receptors by administering atherapeutically effective amount of optically pure (+) norcisapride, ora pharmaceutically acceptable salt thereof, with a therapeuticallyeffective amount of either a proton pump inhibitor or an H₂ receptorantagonist.

The invention encompasses methods of preventing, treating, or managingGERD, emesis, gastrointestinal motility dysfunction, gastrointestinalulcers, pathological hypersecretory conditions, or gastric hyperaciditywhich comprise administering to a patient a therapeutically effectiveamount of optically pure (+) norcisapride, or a pharmaceuticallyacceptable salt thereof, with either a proton pump inhibitor or an H₂receptor antagonist. In specific embodiments, the invention alsoencompasses the use of these agents in combination for preventing,treating, or managing erosive esophagitis, dyspepsia, gastroparesis,constipation, post-operative ileus, intestinal pseudo obstruction,gastric ulcers, duodenal ulcers, heartburn, acid indigestion, erosiveesophagitis, sour stomach, upset stomach, and Zollinger-EllisonSyndrome.

The invention, which encompasses the use of triple action therapy, mayoptionally further include the use of one or more additional therapeuticagents known to treat gastrointestinal disorders. Examples of suchadditional therapeutic agents include, but are not limited to,hydroxyzine (ANTARAX®); diphenhydramine (BENADRYL PARENTAREL®);prochlorperazine (COMPAZINE®); dronabinol (MARINOL®); promethazine(PHENERGAN®); meclizine (ANTIVERT®); trimethobenzamide (TIGAN®);thiethylperazine (TORECAN®); perphenazine (TRILAFON®); sucralfate(CARAFATE®); and the like, and where applicable, optically purestereoisomers or active metabolites thereof.

The administration of two or more therapeutic agents used in accordancewith the methods of the invention may be concurrent, sequential, orboth, i.e., optically pure (+) norcisapride, or a pharmaceuticallyacceptable salt thereof, and either a proton pump inhibitor or an H₂receptor antagonist, and optionally an additional therapeutic agent, maybe administered as a combination, concurrently but separately, or bysequential administration.

The methods and compositions of this invention are considered to providethe benefit of reducing or avoiding adverse effects associated withprior methods and compositions used in the treatment of gastrointestinaldisorders. See, e.g. Physician's Desk Reference®, Medical Economics Co.,Inc., 52^(nd) Edition (1998 and 1999).

The terms “adverse effects” and “adverse side effects,” as used herein,include, but are not limited to, cardiac arrhythmia, cardiac conductiondisturbances, appetite stimulation, weight gain, sedation,gastrointestinal distress, headache, dry mouth, constipation, diarrhea,and drug-drug interactions. The term “cardiac arrhythmia” includes, butis not limited to, ventricular tachyrhythmia, torsades de pointes, Q_(T)prolongation, and ventricular fibrillation.

The term “gastrointestinal disorder,” as used herein, includes, but isnot limited to, gastrointestinal motility dysfunction, GERD, emesis,gastrointestinal ulcers, pathological hypersecretory conditions, gastrichyperacidity, erosive esophagitis, dyspepsia, gastroparesis,constipation, post-operative ileus, intestinal pseudo obstruction,gastric ulcers, duodenal ulcers, heartburn, acid indigestion, erosiveesophagitis, sour stomach, upset stomach, and Zollinger-EllisonSyndrome.

The term “patient,” as used herein, refers to a mammal, particularly ahuman.

The term “racemic,” as used herein, is defined as a mixture of the (+)and (−) enantiomers of a compound wherein the (+) and (−) enantiomersare present in approximately a 1:1 ratio.

The phrase “optically pure,” as used herein, means that the compositioncontains greater than about 90% of the desired stereoisomer by weight,preferably greater than about 95% of the desired stereoisomer by weight,and more preferably greater than about 99% of the desired stereoisomerby weight, based upon the total weight of the active ingredient, e.g.,norcisapride when used to qualify (+) norcisapride. The term“substantially free,” as used herein, means less than about 10 weightpercent, preferably less than about 5 weight percent, and morepreferably less than about 1 weight percent of the undesiredstereoisomer, e.g., (−) norcisapride, is present according to theinvention.

The phrase “5-HT₃ receptor antagonist,” as used herein, means a compoundcapable of binding reversibly to a Type-3 5-hydroxytryptamine receptor.5-HT₃ receptor antagonists include, but are not limited to, granisetron(KYTRIL®), metoclopramide (REGLAN®), ondansetron (ZOFRAN®), renzapride,zacopride, tropisetron, and where applicable, optically purestereoisomers or active metabolites thereof.

The phrase “5-HT₄ receptor agonist,” as used herein, means a compoundcapable of binding reversibly to a Type-4 5-hydroxytryptamine receptor.5-HT₄ receptor agonists include, but are not limited to, norcisaprideand cisapride, and where applicable, optically pure stereoisomers oractive metabolites thereof.

The phrase “proton pump,” as used herein, refers to H⁺-K⁺ ATPase, amembrane-bound enzyme that facilitates active transport of H⁺ acrossmembranes against a concentration gradient.

The phrase “proton pump inhibitor,” as used herein, refers to any agentor compound that inhibits or suppresses gastric acid secretion byinhibition of the H⁺-K⁺ ATPase enzyme system at the secretory surface ofgastric parietal cells. Proton pump inhibitors include, but are notlimited to, prazole derivatives, such as omeprazole lansoprazole,pantoprazole, rabeprazole, and where applicable, optically purestereoisomers such as optically pure (+) lansoprazole, optically pure(−) lansoprazole, optically pure (+) omeprazole, optically pure (−)omeprazole, optically pure (+) rabeprazole, optically pure (−)rabeprazole, optically pure (+) pantoprazole and optically pure (−)pantoprazole, or active metabolites thereof. Active metabolites ofproton pump inhibitors suitable for use according to the inventioninclude, but are not limited to, hydroxy-omeprazole,hydroxy-lansoprazole, the carboxylic acid derivative of omeprazole, anddesmethyl-pantoprazole, and where applicable, optically purestereoisomers thereof. Omeprazole, lansoprazole, pantoprazole, andrabeprazole, for example, may be prepared by syntheses known to those ofordinary skill in the art, particularly from U.S. Pat. Nos. 4,544,750,4,620,008, 4,620,008, 4,758,579, 5,045,552, 5,374,730, 5,386,032,5,470,983, and 5,502,195, the disclosures of which are each incorporatedherein by express reference thereto.

The phrase “H₂ receptor antagonist,” as used herein, refers to any agentor compound that competitively inhibits the interaction of histaminewith H₂ receptors. H₂ receptor antagonists include, but are not limitedto, cimetidine, famotidine, ranitidine, nizatidine, and whereapplicable, optically pure stereoisomers or active metabolites thereof.Active metabolites of H₂ receptor antagonists include, but are notlimited to, N2-monodesmethylnizatidine and where applicable, opticallyactive stereoisomers thereof

Nizatidine may be prepared by synthesis known to those of ordinary skillin the art, particularly from U.S. Pat. Nos. 5,541,335 and 5,700,945,the disclosures of which are each incorporated herein by expressreference thereto. Ranitidine may be prepared by synthesis known tothose of ordinary skill in the art, particularly from U.S. Pat. No.5,118,813, the disclosure of which is each incorporated herein byexpress reference thereto. Cimetidine may be prepared by synthesis knownto those of ordinary skill in the art, particularly from U.S. Pat. Nos.4,413,129, 4,855,439, 4,886,910, 4,886,912, and 5,118,813, thedisclosures of which are each incorporated herein by express referencethereto. Moreover, famotidine may be prepared by synthesis known tothose of ordinary skill in the art, described in, for example,Guimaraens et al., Contact Dermatitis, 31(4):259 (1994).

The diseases prevented, treated, or managed in the invention are hereinused consistently according to Stedman's Medical Dictionary, 26^(th)Edition, Williams and Wilkins (1995).

The terms “gastro-esophageal reflux disease” or “GERD,” as used herein,is defined as a condition characterized by the backward flow of thestomach contents into the esophagus.

The term “gastrointestinal ulcer,” as used herein, is defined as acondition characterized by a lesion or lesions on the surface of thelining of the gastrointestinal tract, caused by superficial loss oftissue, usually accompanied by inflammation. Gastrointestinal ulcersinclude, but are not limited to, duodenal ulcers, and gastric ulcers.

The phrase “erosive esophagitis,” as used herein, is defined as acondition characterized by inflammation of the lower esophagus fromregurgitation of acid gastric contents, usually due to malfunction ofthe lower esophogeal sphincter.

The term “dyspepsia,” as used herein, is defined as a conditioncharacterized by an impairment of the power or function of digestionthat can arise as a symptom of primary gastrointestinal dysfunction oras a complication due to other disorders, such as appendicitis,gallbladder disturbances, or malnutrition.

The term “gastroparesis,” as used herein, is defined as a paralysis ofthe stomach brought about by a motor abnormality in the stomach or as acomplication of diseases, such as diabetes, progressive systemicsclerosis, anorexia nervosa, or myotonic dystrophy.

The term “constipation,” as used herein, is defined as a conditioncharacterized by infrequent or difficult evacuation of feces resultingfrom conditions, such as lack of intestinal muscle tone or intestinalspasticity.

The phrase “post-operative ileus,” as used herein, is defined as anobstruction in the intestine due to a disruption in muscle tonefollowing surgery.

The terms “preventing” and “prevention,” as used herein, are definedrespectively as to stop or hinder and the act of stopping or hinderingconditions or disorders in a patient who is at risk of suffering fromsuch conditions or disorders, including, but not limited to, patientswho suffer from stress.

The phrase “intestinal pseudo-obstruction,” as used herein, is definedas a condition characterized by constipation, colicky pain, andvomiting, but without evidence of physical obstruction.

The phrase “gastric hyperacidity,” as used herein, is defined as acondition characterized by an abnormally high degree of acidity in thegastric juices.

The phrase “therapeutically effective amount,” as used herein, isdefined as that amount of a therapeutic agent, which, alone or incombination with other drugs, provides a therapeutic benefit in theprevention, treatment, or management of gastrointestinal disorders, butnot limited to, gastrointestinal motility dysfunction, GERD, emesis,gastrointestinal ulcers, pathological hypersecretory conditions, gastrichyperacidity, or symptoms thereof. Different therapeutically effectiveamounts may be applicable for each disorder, as will be readily known bythose of ordinary skill in the art.

Optically pure (+) norcisapride may be obtained from a racemic mixtureof cisapride, the chemical synthesis of which can be performed accordingto the method described in European Patent Application No. 0,076,530 A2published Apr. 13, 1983, or U.S. Pat. Nos. 4,962,115, 5,057,525 or5,137,896, the disclosures of which are each incorporated herein byexpress reference thereto. See also, Van Daele, et al., Drug DevelopmentRes., 8:225-232 (1986). The metabolism of cisapride to norcisapride isdescribed in Meuldermans, W., et al., Drug Metab. Dispos., 16(3):410-419(1988) and Meuldermans, W., et al., Drug Metab. Dispos., 16(3):403-409(1988). The preparation of racemic norcisapride is also known to thoseof ordinary skill in the art, particularly in view of EP 0,076,530 A2and U.S. Pat. No. 5,137,896 to Van Daele, the disclosures of which areeach incorporated herein by express reference thereto. Optically purestereoisomers of the chiral compounds discussed herein may also beobtained from the racemic mixture by resolution of the enantiomers usingconventional means, for example, from an optically active resolvingacid. The resolution of racemic compounds is also known to those ofordinary skill in the art, particularly from Jacques, J., et al.,Enantiomers, Racemates and Resolutions, Wiley-Interscience, New York(1981); Wilen, S. H., et al., Tetrahedron, 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds, McGraw-Hill, NY, (1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, E. L. Eliel, Ed.,Univ. of Notre Dame Press, Notre Dame, Ind., p. 268 (1972).

In addition to separation techniques, such as those described above,optically pure compounds may be synthesized by stereospecific synthesisusing methodology well known to those of ordinary skill in the art.Chiral synthesis can result in products of high enantiomeric purity.However, in some cases, the enantiomeric purity of the product is notsufficiently high. The skilled artisan will appreciate that theseparation methods described above may be used to further enhance theenantiomeric purity of the active stereoisomers which are obtained bychiral synthesis.

For example, optically pure (+) norcisapride may also be prepared fromthe racemic norcisapride mixture by enzymatic biocatalytic resolution.This synthesis is known to those of ordinary skill in the art,particularly from U.S. Pat. Nos. 5,057,427 and 5,077,217, thedisclosures of which are each incorporated herein by express referencethereto.

The magnitude of a prophylactic or therapeutic dose of the activeingredients discussed herein, e.g., (+) norcisapride, a 5-HT₃antagonist, a 5-HT₄ agonist or antagonist, a proton pump inhibitor, oran H₂ receptor antagonist, in the acute or chronic management ofdiseases and disorders described herein, will vary with the nature andseverity of the condition to be prevented, treated, or managed and theroute of administration. For example, oral, mucosal (including rectal),parenteral (including subcutaneous, intramuscular, bolus injection, andintravenous), sublingual, transdermal, nasal, buccal, and like may beemployed. Dosage forms include tablets, caplets, troches, lozenges,dispersions, suspensions, suppositories, solutions, capsules, softelastic gelatin capsules, patches, and the like. The dose, and perhapsthe dose frequency, will also vary according to the age, body weight,and response of the individual patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors.

In general, the total daily dosage of a 5-HT₃ receptor antagonist, a5-HT₄ receptor agonist, or a therapeutic agent providing dual action at5-HT₃ receptors and 5-HT₄ receptors for the conditions described herein,is from about 0.5 mg to about 500 mg, preferably from about 1 mg toabout 350 mg, and more preferably from about 2 mg to about 250.

Suitable daily dosage ranges of proton pump inhibitors can be readilydetermined by those skilled in the art. In general the total dailydosage of a proton pump inhibitor for the conditions described herein,such as lansoprazole, pantoprazole, rabeprezole, omeprazole, oroptically pure stereoisomers or active metabolites thereof, is fromabout 1 mg to about 200 mg, preferably from about 5 mg to about 150 mg,and more preferably from about 10 mg to about 100 mg.

In addition, suitable daily dosage ranges of H₂ receptor antagonists canbe readily determined by those skilled in the art. For example, see thePhysician 's Desk Reference®, Medical Economics Co., Inc., 52^(nd)Edition (1999) for suitable dosages presently used for known H₂ receptorantagonists. For example, ranitidine may be administered using an oraldaily dose range from about 1 mg to about 800 mg, preferably from about100 mg to about 600 mg, and more preferably from about 250 mg to about500 mg. For cimetidine, the oral daily dose range may be from about 1 mgto about 2400 mg, preferably from about 400 mg to about 1600 mg, morepreferably from about 600 mg to about 1000 mg. For famotidine, the oraldaily dose range may be from about 1 mg to about 200 mg, preferably fromabout 10 mg to about 80 mg, more preferably from about 15 mg to about 50mg. For nizatidine, the oral daily dose range may be from about 1 mg toabout 600 mg, preferably from about 50 mg to about 500 mg, morepreferably from about 250 mg to about 350 mg.

In managing the patient, the therapy may be initiated at a lower dose,e.g., from about 0.5 mg to about 10 mg of (+) norcisapride and fromabout 1 mg to about 5 mg of a proton pump inhibitor or from about 1 mgto about 5 mg of an H₂ receptor antagonist, and increased up to therecommended daily dose or higher depending on the patient's globalresponse. It is further recommended that children, patients over 65years, and those with impaired renal or hepatic function, initiallyreceive low doses, and that they be titrated based on individualresponse(s) and blood level(s). It may be necessary to use dosages ofeach active ingredient outside the ranges disclosed herein in somecases, as will be apparent to those of ordinary skill in the art.Furthermore, it is noted that the clinician or treating physician willknow how and when to interrupt, adjust, or terminate therapy inconjunction with individual patient response.

Pharmaceutical compositions for use in the present invention cancomprise a 5-HT₃ receptor antagonist and 5-HT₄ receptors agonist, or atherapeutic agent providing dual action at 5-HT₃ receptors and 5-HT₄receptors with either a proton pump inhibitor or H₂ receptor antagonistas the active ingredients, and may additionally contain apharmaceutically acceptable carrier, and optionally, other therapeuticingredients.

In one embodiment, the pharmaceutical compositions comprise threetherapeutic agents, a 5-HT₃ receptor antagonist and a 5-HT₄ receptoragonist with a proton pump inhibitor or H₂ receptor antagonist, and mayadditionally contain a pharmaceutically acceptable carrier, andoptionally, other therapeutic ingredients. In a preferred embodiment,the pharmaceutical compositions comprise two therapeutic agents, oneproviding dual action at 5-HT₃ receptors and 5-HT₄ receptors, and theother is either a proton pump inhibitor or H₂ receptor antagonist.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from pharmaceutically acceptable non-toxic acidsincluding, but not limited to inorganic acids, organic acids, solvates,hydrates, or clathrates thereof. Examples of such inorganic acids arehydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric.Appropriate organic acids may be selected, for example, from aliphatic,aromatic, carboxylic and sulfonic classes of organic acids, examples ofwhich are formic, acetic, propionic, succinic, benzoic camphorsulfonic,citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric,para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic,benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic,stearic, sulfanilic, alginic, galacturonic, and the like. Particularlypreferred acids are hydrobromic, hydrochloric, phosphoric, and sulfuricacids. In one embodiment, a 5-HT₃ receptor antagonist, a 5-HT₄ receptoragonist, or a therapeutic agent providing dual action as a 5-HT₃receptor antagonist and a 5-HT₄ receptor agonist are administered as thefree base or hydrate. For example, optically pure (+) norcisapride isadministered as a free base or hydrate.

The invention also contemplates the use of active agents or compoundsthat are acidic, in which salts may be prepared from pharmaceuticallyacceptable non-toxic bases including organic, inorganic bases, solvates,hydrates, or clathrates thereof. Such inorganic bases include, but arenot limited to, metallic salts of aluminum, calcium, lithium, magnesium,potassium, sodium, and zinc. Appropriate organic bases include, but arenot limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine,and procaine.

In practical use, the active agents in the pharmaceutical compositionsof the invention can be combined as the active ingredients in intimateadmixture with a pharmaceutically acceptable carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms and comprises a number of components dependingon the form of preparation desired for administration. The compositionsof the present invention include, but are not limited to, suspensions,solutions and elixirs; aerosols; or excipients, including, but notlimited to, starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike. Preferably, the pharmaceutical composition is in the form of anoral preparation. Because of their ease of administration, tablets andcapsules are preferred and represent the most advantageous oral dosageunit form, in which case solid pharmaceutical excipients are employed.If desired, tablets may be coated by standard aqueous or nonaqueoustechniques.

Preferably, the oral pharmaceutical compositions of the presentinvention may be administered in single or divided doses, from one tofour times a day. The oral dosage forms may be conveniently presented inunit dosage forms and prepared by any methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete pharmaceutical unit dosageforms, such as capsules, cachets, soft elastic gelatin capsules,tablets, caplets, or aerosols sprays, each containing a predeterminedamount of the active ingredients, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any methods well known in the art ofpharmacy, but all methods include the step of bringing into associationone or more active ingredient(s) with the carrier. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. Oral solid preparations are preferred over oral liquidpreparations. One preferred oral solid preparation is capsules, but themost preferred oral solid preparation is tablets.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form, such as powder or granules,optionally mixed with a binder, lubricant, inert diluent, granulatingagent, surface active or dispersing agent, or the like. Molded tabletsmay be made by molding, in a suitable machine, a mixture of the powderedcompound moistened with an inert liquid diluent. Preferably, eachtablet, cachet, caplet, or capsule contains from about 0.5 mg to about500 mg of optically pure (+) norcisapride, more preferably from about 1mg to about 350 mg, in combination with from about 1 mg to about 200 mgof a proton pump inhibitor or from about 1 mg to about 2400 mg of an H₂receptor antagonist.

Pharmaceutical compositions of the present invention suitable for oraladministration may be formulated as a pharmaceutical composition in asoft elastic gelatin capsule unit dosage form by using conventionalmethods well known in the art. See, e.g., Ebert, Pharm. Tech, 1(5):44-50(1977). Soft elastic gelatin capsules have a soft, globular gelatinshell somewhat thicker than that of hard gelatin capsules, wherein agelatin is plasticized by the addition of plasticizing agent, e.g.,glycerin, sorbitol, or a similar polyol. The hardness of the capsuleshell may be changed by varying the type of gelatin used and the amountsof plasticizer and water. The soft gelatin shells may contain apreservative, such as methyl- and propylparabens and sorbic acid, toprevent the growth of fungi. The active ingredient may be dissolved orsuspended in a liquid vehicle or carrier, such as vegetable or mineraloils, glycols, such as polyethylene glycol and propylene glycol,triglycerides, surfactants, such as polysorbates, or a combinationthereof.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans or delivery devices that are well known to those of ordinary skillin the art, such as those described in U.S. Pat. Nos.: 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566,the disclosures of which are each incorporated herein by expressreference thereto. These pharmaceutical compositions can be used toprovide slow or controlled-release of one or more of the activeingredients therein using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or thelike, or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,may be readily selected for use with the pharmaceutical compositions ofthe invention. Thus, single unit dosage forms suitable for oraladministration, such as tablets, capsules, gelcaps, caplets, and thelike, that are adapted for controlled-release are encompassed by thepresent invention.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations may include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effect,and gradually and continually release of other amounts of drug tomaintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.

The controlled-release of an active ingredient may be stimulated byvarious inducers, for example pH, temperature, enzymes, water, or otherphysiological conditions or compounds. The term “controlled-releasecomponent” in the context of the present invention is defined herein asa compound or compounds, including, but not limited to, polymers,polymer matrices, gels, permeable membranes, liposomes, microspheres, orthe like, or a combination thereof, that facilitates thecontrolled-release of the active ingredient.

Pharmaceutical compositions of the present invention may also beformulated for parenteral administration by injection (subcutaneous,bolus injection, intramuscular, or intravenous), and may be dispensed ina unit dosage form, such as a multidose container or an ampule. Suchcompositions for parenteral administration may be in the form ofsuspensions, solutions, emulsions, or the like in aqueous or oilyvehicles, and in addition to the active ingredients may contain one ormore formulary agents, such as dispersing agents, suspending agents,stabilizing agents, preservatives, and the like.

Another route of administration is transdermal delivery, for example,via an abdominal skin patch.

The invention is further defined by reference to the following examples,describing in detail the preparation of the compound and thecompositions of the present invention, as well as their utility. It willbe apparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from thepurpose and interest of this invention.

EXAMPLES 5.1 Example 1 Receptor Binding 5-HT₃ Receptor

Racemic norcisapride, racemic cisapride and their (+)- and (−)-stereoisomers were tested (Cerep, Celle l'Evescault, France) for bindingto 5-HT₃ receptor subtypes derived from N1E-115 cells.

Following incubation with the appropriate ligands, the preparations wererapidly filtered under vacuum through GF/B glass fiber filters andwashed with ice-cold buffer using a Brandel or Packard cell harvester.Bound radioactivity was determined with a liquid scintillation counter(LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989).

Specific radioligand binding to the receptor was defined as thedifference between total binding and nonspecific binding determined inthe presence of an excess of unlabeled ligand. Results were expressed asa percent inhibition of specific binding obtained in the presence of thecompounds. IC₅₀ were determined using concentrations ranging from3×10⁻¹⁰ M to 10⁻⁵ M to obtain full competition curves and werecalculated by non-linear regression analysis. The results are shown inTables 3 and 4 below.

Other active ingredients, such as granisetron, metoclopramide,ondansetron, renzapride, zacopride, tropisetron, and the like, can betested using the methods described above.

5-HT₄ Receptor

Racemic norcisapride, racemic cisapride and their (+)- and (−)-stereoisomers were tested (Cerep, Celle l'Evescault, France) for bindingto 5-HT₄ receptor subtypes derived from guinea-pig striata.

Following incubation with the appropriate ligands, the preparations wererapidly filtered under vacuum through GF/B glass fiber filters andwashed with ice-cold buffer using a Brandel or Packard cell harvester.Bound radioactivity was determined with a liquid scintillation counter(LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989).

Specific radioligand binding to the receptor was defined as thedifference between total binding and nonspecific binding determined inthe presence of an excess of unlabeled ligand. Results were expressed asa percent inhibition of specific binding obtained in the presence of thecompounds. IC₅₀ were determined using concentrations ranging from3×10⁻¹⁰ M to 10⁻⁵ M to obtain full competition curves and werecalculated by non-linear regression analysis. The results are shown inTables 3 and 4 below.

Other active ingredients, such as cisapride and the like, can be testedusing the methods described above.

TABLE 3 IC₅₀ (nM) Values for Binding to 5-HT₃ and 5-HT₄ Sites 5-HT₃/Compound 5-HT₃ 5-HT₄ 5-HT₄ Ratio (±) Norcisapride 8.2 686 0.012 (+)Norcisapride 4.5 33l 0.014 (−) Norcisapride 30.4 1350 0.023

TABLE 4 IC₅₀ (nM) Values for Binding to 5-HT₃ and 5-HT₄ Sites 5-HT₃/Compound 5-HT₃ 5-HT₄ 5-HT₄ Ratio (±) Cisapride 365 169 2.2 (+) Cisapride310 340 0.9 (−) Cisapride 2790 199 14.0

Agonist activity at 5-HT₄ receptor sites may also be assessed using anassay based on the ability of active compounds to increase cyclic AMPproduction in mouse embryo colloculi neurones grown in tissue culture(See Dumuis et al., N. S. Arch. Pharmacol., 340:403-410 (1989)).

5.2 Example 2 Oral Formulation

Tablets Quantity per Tablet in mg. Formula A B C Active Ingredients: 5.010.0 25.0 (+) Norcisapride Lansoprazole 5.0 15.0 30.0 Lactose BP 57.092.0 107.0 Starch BP 20.0 20.0 25.0 Microcrystalline Cellulose 10.0 10.010.0 Hydrogenated Vegetable Oil 1.5 1.5 1.5 Polyvinylpyrrolidinone 1.51.5 1.5 Compression Weight 100.0 150.0 200.0

The active ingredients, (+) norcisapride and lansoprazole, are sievedthrough a suitable sieve and blended with the lactose until a uniformblend is formed. Suitable volumes of water are added and the powders aregranulated. After drying, the granules are then screened and blendedwith the remaining excipients. The resulting granules are thencompressed into tablets of desired shape. Tablets of other strengths maybe prepared by altering the ratio of active ingredient to theexcipient(s) or the compression weight.

Tablets Quantity per Tablet in mg. Formula A B C Active Ingredients: 5.010.0 25.0 (+) Norcisapride Famotidine 10.0 20.0 40.0 Lactose BP 38.573.5 43.5 Starch BP 30.0 30.0 60.0 Pregelatinized Maize Starch BP 15.015.0 30.0 Magnesium Stearate BP 1.5 1.5 1.5 Compression Weight 100.0150.0 540.0

The active ingredients, (+) norcisapride and famotidine, are sievedthrough a suitable sieve and blended with lactose, starch, andpregelatinized maize starch until a uniform blend is formed. Suitablevolumes of water are added and the powders are granulated. After drying,the granules are then screened and blended with the remainingexcipients. The resulting granules are then compressed into tablets ofdesired shape. Tablets of other strengths may be prepared by alteringthe ratio of active ingredient to the excipient(s) or the compressionweight.

Tablets Quantity per Tablet in mg. Formula A B C Active Ingredients: 5.010.0 25.0 (+) Norcisapride Lactose BP 48.5 43.5 78.5 Starch BP 30.0 30.030.0 Pregelatinized Maize Starch BP 15.0 15.0 15.0 Magnesium Stearate BP1.5 1.5 1.5 Compression Weight 100.0 100.0 150.0

The active ingredient, (+) norcisapride, is sieved through a suitablesieve and blended with lactose, starch, and pregelatinized maize starchuntil a uniform blend is formed. Suitable volumes of water are added andthe powders are granulated. After drying, the granules are then screenedand blended with the remaining excipients. The resulting granules arethen compressed into tablets of desired shape. Tablets of otherstrengths may be prepared by altering the ratio of active ingredient tothe excipient(s) or the compression weight.

While the present invention has been described with respect to theparticular embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made without departingfrom the spirit and scope of the invention as defined in the claims.Such modifications are also intended to fall within the scope of theappended claims.

What is claimed is:
 1. A method of treating gastrointestinal disordersin a patient which comprises administering to said patient atherapeutically effective amount of (+) norcisapride, or apharmaceutically acceptable salt thereof, substantially free of its (−)stereoisomer, and a therapeutically effective amount of at least one ofa proton pump inhibitor, an H₂ receptor antagonist, or an optically purestereoisomer or an active metabolite thereof, or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein the patientis a human.
 3. The method of claim 1, wherein the gastrointestinaldisorder is gastrointestinal motility dysfunction.
 4. The method ofclaim 3, wherein the gastrointestinal motility dysfunction is selectedfrom the group consisting of dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo obstruction.
 5. The methodof claim 1, wherein the gastrointestinal disorder is gastro-esophagealreflux disease, emesis, gastrointestinal ulcers, pathologicalhypersecretory condition, and gastric hyperacidity.
 6. The method ofclaim 5, wherein the pathological hypersecretory condition isZollinger-Ellison Syndrome.
 7. The method of claim 5, wherein thegastric hyperacidity is selected from the group consisting of heartburn,acid indigestion, sour stomach, erosive esophagitis, and upset stomach.8. The method of claim 1, wherein the amount of (+) norcisaprideadministered is from about 0.5 mg to about 500 mg.
 9. The method ofclaim 8, wherein the amount of (+) norcisapride administered is fromabout 1 mg to about 350 mg.
 10. The method of claim 1, wherein theproton pump inhibitor is administered and is selected from the groupconsisting of omeprazole, lansoprazole, rabeprazole, pantoprazole,hydroxy-omeprazole, desmethyl-pantoprazole, hydroxy-lansoprazole, and anoptically pure stereoisomer thereof.
 11. The method of claim 10, whereinthe amount of proton pump inhibitor is from about 1 mg to about 200 mg.12. The method of claim 11, wherein the amount of proton pump inhibitoris from about 5 mg to about 150 mg.
 13. The method of claim 1, whereinthe H₂ receptor antagonist is administered and is selected from thegroup consisting of cimetidine, ranitidine, famotidine, nizatidine, andan optically pure stereoisomer or an active metabolite thereof.
 14. Themethod of claim 13, wherein the amount of H₂ receptor antagonist is fromabout 1 mg to about 2400 mg.
 15. The method of claim 1, wherein at leastone of (+) norcisapride and the proton pump inhibitor is administeredorally.
 16. The method of claim 15, herein (+) norcisapride and theproton pump are orally administered as a tablet or a capsule.
 17. Themethod of claim 1, wherein at least one of (+) norcisapride and the H₂receptor antagonist is administered orally.
 18. The method of claim 1,wherein the proton pump inhibitor or the H₂ receptor antagonist isadministered together with (+) norcisapride parenterally, transdermally,rectally or sublingually.
 19. The method of claim 1, which comprisesadministering either the proton pump inhibitor or H₂ receptorantagonist, and the (+) norcisapride, concurrently or sequentially. 20.A method of preventing or managing gastrointestinal disorders in apatient in need thereof, which comprises administering to said patient atherapeutically effective amount of (+) norcisapride, or apharmaceutically acceptable salt thereof, substantially free of its (−)stereoisomer, and a therapeutically effective amount of at least one ofa proton pump inhibitor, an H₂ receptor antagonist, or an optically purestereoisomer or an active metabolite thereof, or a pharmaceuticallyacceptable salt thereof.
 21. A pharmaceutical composition adapted forthe treatment of a patient suffering from a gastrointestinal disorderwhich comprises a therapeutically effective amount of (+) norcisapride,or a pharmaceutically acceptable salt thereof, substantially free of its(−) stereoisomer; and a therapeutically effective amount of at least oneof a proton pump inhibitor, H₂ receptor antagonist, or an optically purestereoisomer or an active metabolite thereof, or a pharmaceuticallyacceptable salt thereof.
 22. The pharmaceutical composition of claim 21,wherein the proton pump inhibitor is present and is selected from thegroup consisting of omeprazole, pantoprazole, rabeprazole, lansoprazole,hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic acid derivativeof omeprazole, and desmethyl-pantoprazole.
 23. The pharmaceuticalcomposition of claim 21, wherein the H₂ receptor antagonist is presentand is selected from the group consisting of cimetidine, ranitidine,famotidine, nizatidine, and N2-desmethylnizatidine.